{"doi":"10.1136/jitc-2021-003459","title":"CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of T<sub>H</sub>1 and T<sub>H</sub>9 cells","abstract":"Background While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive. Methods Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances T H 9 cell antitumor activity against mouse melanoma upon adoptive transfer. Results We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of T H 1 and T H 9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of T H 1 cell differentiation. However, STING activation favors T H 9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on T H 1 and T H 9-derived cytokines, and STING activation enhances the antitumor activity of T H 9 cells upon adoptive transfer. Conclusion Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.","journal":"Journal for ImmunoTherapy of Cancer","year":2022,"id":235152,"datarank":0.6663976884735476,"base_score":4.442651256490317,"endowment":4.442651256490317,"self_citation_contribution":0.6663976884735476,"citation_network_contribution":0.0,"self_endowment_contribution":0.6663976884735476,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":84,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":852725,"name":"Élise Jacquin","orcid":"0000-0003-0368-4113","position":1,"is_corresponding":false},{"id":853750,"name":"Thaiz Rivera Vargas","orcid":null,"position":2,"is_corresponding":false},{"id":91572,"name":"Corentin Richard","orcid":"0000-0001-9732-0219","position":3,"is_corresponding":false},{"id":853751,"name":"Aurélie Roussey","orcid":null,"position":4,"is_corresponding":false},{"id":852726,"name":"Didier Ducloux","orcid":"0000-0003-3841-1211","position":5,"is_corresponding":false},{"id":671199,"name":"Tiffany Martin","orcid":"0000-0002-9258-4861","position":6,"is_corresponding":false},{"id":853752,"name":"Andréa Melis","orcid":null,"position":7,"is_corresponding":false},{"id":852727,"name":"Daria Vinokurova","orcid":"0000-0002-8422-8349","position":8,"is_corresponding":false},{"id":284354,"name":"Sayyed Hamed Shahoei","orcid":"0009-0001-0625-2677","position":9,"is_corresponding":false},{"id":852728,"name":"Alvaro Baeza Garcia","orcid":"0000-0001-6032-7847","position":10,"is_corresponding":false},{"id":853753,"name":"Cassandre Pignol","orcid":null,"position":11,"is_corresponding":false},{"id":852729,"name":"Stéphane Giorgiutti","orcid":"0000-0002-4791-9618","position":12,"is_corresponding":false},{"id":852730,"name":"Raphaël Carapito","orcid":"0000-0002-7036-442X","position":13,"is_corresponding":false},{"id":839100,"name":"Romain Boidot","orcid":"0000-0001-9956-1737","position":14,"is_corresponding":false},{"id":852731,"name":"Frédérique Végran","orcid":"0000-0002-4377-1441","position":15,"is_corresponding":false},{"id":80236,"name":"Richard A. 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